Pseudocholinesterase Deficiency
Autosomal recessive (BCHE gene mutation).
Pathophysiology: ↓ or absent pseudocholinesterase activity → slow succinylcholine metabolism → ↑ drug at NMJ → prolonged paralysis.
Clinical:
Failure to resume spontaneous respiration post-intubation.
Prolonged weakness of voluntary muscles.
Heterozygotes: paralysis ~2× normal duration.
Homozygotes: paralysis for several hours.
Other drugs affected: mivacurium (nondepolarizing NM blocker), cocaine.
Train-of-Four (TOF) & Neuromuscular Blockers
TOF principle – Stimulate a peripheral nerve 4 times in quick succession → record muscle twitches.
1) Nondepolarizing blockers (eg, vecuronium):
MOA: Competitive inhibition of postsynaptic nicotinic ACh receptors → ↓ muscle fiber activation.
TOF: Progressive fade in twitch height (1st twitch stronger, later twitches weaker) due to:
Postsynaptic blockade
Presynaptic ACh receptor blockade → ↓ ACh release with repeated stimulation.
2) Depolarizing blocker (eg, succinylcholine):
Phase I block: Persistent depolarization → equal reduction in all 4 twitches (no fade).
Phase II block: With prolonged exposure → receptor desensitization → fade pattern like nondepolarizing agents.
Duration of action: Normally <10 min (rapid metabolism by plasma pseudocholinesterase).
3) Pseudocholinesterase deficiency (autosomal recessive, BCHE gene mutation):
Slow breakdown → ↑ succinylcholine at NMJ → paralysis for hours.
Also prolongs mivacurium & cocaine effects.
Requires mechanical ventilation until recovery.
hepatic cytochrome
Theophylline is an adenosine receptor antagonist and indirect adrenergic agent with a narrow therapeutic index. It is predominantly metabolized by the hepatic cytochrome oxidases. Inhibition of these enzymes by concurrent illness (eg, infection with fever) or ingestion of certain drugs or substances (eg, ciprofloxacin) can raise serum theophylline concentrations and cause toxicity (eg, seizures, cardiac arrhythmias).
rapid sequence induction
1)Propofol
MOA: Highly lipophilic GABA agonist.
Advantages: Reduces airway resistance.
Disadvantages:
Vasodilation → hypotension.
↑ Serum triglycerides & lipase.
2) Etomidate
MOA: GABA agonist.
Advantages:
Most hemodynamically neutral (no change in HR, BP, CO).
Disadvantages:
Inhibits cortisol synthesis → reversible adrenocortical suppression.
Avoid in septic shock.
Not for prolonged sedation after induction.
3)Ketamine
MOA: NMDA antagonist (PCP analog).
Advantages:
Preserves respiratory drive.
Provides analgesia.
Catecholamine release → ↑ HR, ↑ contractility, bronchodilation.
Disadvantages:
↑ Myocardial oxygen demand.
↑ Cerebral blood flow & ICP.
Clinical choice in hypotension:
Use etomidate (hemodynamically neutral) or ketamine (can increase BP via catecholamines).
beta-2 agonists
Short-acting beta-2 agonists (eg, albuterol, levalbuterol) are hydrophilic and are rapidly metabolized, explaining their rapid onset and short duration of action.
Long-acting beta-2 agonists (eg, salmeterol, formoterol) have a prolonged duration of action due to their lipophilic side chain, which allows them to attach to the cell plasma membrane.
Salmeterol also binds to a secondary exosite within the beta-2 receptor, anchoring the molecule and further prolonging its action.
empyema
Drainage with a chest tube is often difficult due to loculations and high fluid viscosity, but it can be aided by the intrapleural administration of a fibrinolytic agent (eg, tissue plasminogen activator) in combination with a nucleic acid cleaving enzyme (ie, deoxyribonuclease).
corticosteroids
Corticosteroids reduce inflammation by inhibiting nuclear transcription of inflammatory genes (in part leading to downregulation of the enzyme phospholipase A2) to decrease the production of leukotrienes and other inflammatory mediators.
Although corticosteroids have no direct effect on bronchodilation, these drugs provide an additional benefit in asthma by potentiating the bronchodilatory effect of beta-2 agonists (eg, albuterol). This is accomplished by stimulating the upregulation of beta-2 receptors in bronchial smooth muscle, increasing cellular responsiveness to adrenergic stimulus. This medication effect is similar to the permissive effect of endogenous cortisol on blood pressure, which involves upregulation of alpha-1 receptors and increased responsiveness of vascular smooth muscle cells to epinephrine.
Quitting smoking -Varenicline
The reinforcing effects of nicotine that lead to dependence are thought to be caused by stimulation of the alpha-4 beta-2 nicotinic acetylcholine receptor present in the CNS.
Varenicline is a partial agonist of this receptor that competes with nicotine (a full agonist) and prevents it from binding to the receptor.
Because varenicline is a partial agonist, it helps reduce the symptoms of nicotine withdrawal by mildly stimulating the receptor. However, because varenicline is not a full agonist, downstream release of dopamine is modest, resulting in less stimulation of reward pathways than nicotine.
Dextromethorphan (DXM) cough suppressant
Dextromethorphan (DXM) is a popular cough suppressant (antitussive agent) that is readily available over the counter.
Its primary mechanism of action is inhibition of the medullary cough center through sigma (σ) receptor activation. Although structurally very closely related to other opioid morphinans (eg, codeine, morphine), DXM has trivial mu (μ) and delta (δ) opioid receptor affinity. Therefore, classic opioid adverse effects (eg, constipation, respiratory depression, analgesia, sedation) are not seen at therapeutic doses. This favorable pharmacologic profile makes DXM a first-choice agent for cough suppression.
However, DXM also increases serotonin activity in the CNS by decreasing the rate of presynaptic serotonin reuptake and directly stimulating serotonin receptors.
For this reason, DXM abuse can cause serotonin syndrome, manifesting as muscular hypertonia, spasticity (eg, clonus, hyperreflexia), autonomic instability (eg, hyperthermia, hypertension), and encephalopathy.
IMPORTANT :
This potentially fatal condition most often occurs in settings of overdose or accidental drug interaction with other serotonergic drugs (eg, selective serotonin reuptake inhibitors, triptans, monoamine oxidase inhibitors).
Pulmonary hypertension
1️⃣ Endothelin Pathway
Endothelin Receptor Antagonists (ERAs)
Goal: Block endothelin-1 effects → ↓ vasoconstriction, ↓ remodeling
Examples: Bosentan, Ambrisentan, Macitentan (IMPORTANT)
2️⃣ Nitric Oxide (NO)
Goal: Increase cGMP signaling → relax pulmonary vasculature
Phosphodiesterase-5 Inhibitors
Examples: Sildenafil, Tadalafil
3️⃣ Prostacyclin (PGI₂) Pathway
Goal: Mimic or enhance prostacyclin → potent vasodilation, ↓ platelet aggregation, ↓ proliferation
Prostacyclin Analogs
Examples: Epoprostenol (IV), Treprostinil (IV, inhaled, oral), Iloprost (inhaled)
